! PROJECT SUMMARY/ABSTRACT Despite the wide scale adoption of repetitive transcranial magnetic stimulation (rTMS, hereafter simply TMS), we still lack mechanistically-driven biomarkers designed to identify who is most likely to respond, and why. rTMS is indicated for pharmacoresistant depression. It is imperative that we find more precise solutions for these patients given that pharmacoresistant depression can be life threatening: suicide attempts are twice the rate of non-resistant depression. Our objective is to use a prospective design to evaluate cognitive control network connectivity as a predictive biomarker of the clinical effect of repetitive transcranial magnetic stimulation, and as a response biomarker of change with TMS. We have a novel opportunity to address this objective through a systematic evaluation of brain network biomarkers in 100 patients taking part in a Veterans Administration multi- site clinical TMS program. By utilizing the umbrella Clinical rTMS Program, we can standardize delivered parameters to ensure uniformity. Our primary biomarker is functional connectivity of the cognitive control network of the human brain that is central to the regulation of thought and emotion. We will also assess corresponding behavioral performance. Clinical outcomes are symptom severity, suicidality, and quality of life. Biomarkers will be assessed at baseline, after 5 sessions of rTMS (?low dose?) to explore mechanisms of early response, and upon completion of treatment after 30 sessions (?higher dose?). To power the study for an anticipated conservative effect size of at least .25, we will recruit 100 patients participating in the VA Clinical TMS Program. Using standardized stimulation parameters and harmonized neuroimaging procedures, our aims are to 1) probe the putative mechanistic effect of rTMS on promoting cognitive control and to assess whether connectivity of the cognitive control network changes in a dose-dependent manner, 2) to assess whether extent of change in cognitive control network connectivity predicts corresponding change in behavioral performance and, 3) to identify if baseline functional connectivity and behavior, along with early change in connectivity and behavior, predict subsequent outcomes in symptom severity, suicidal ideation, and quality of life. Innovations of our design include 1) adequate power to interrogate imaging markers, 2) standardization to minimize variability, 3) implementation of a longitudinal design to quantify rTMS-related changes in imaging markers, 4) integration of task-evoked and resting state imaging markers and, and 5) establishing the foundations for expanding lessons learned to additional diagnoses and parameters. !